The challenge to produce effective and safe vaccines for the prevalent infectious diseases of humans and animals has become increasingly difficult. In veterinary medicine, evidence implicating vaccines in triggering immune-mediated and other chronic disorders (vaccinosis) is compelling. While some of these problems have been traced to contaminated or poorly attenuated batches of vaccine that revert to virulence, others apparently reflect the host's genetic predisposition to react adversely upon receiving the single (monovalent) or multiple antigen "combo" (polyvalent) products given routinely to animals. Animals of certain susceptible breeds or families appear to be at increased risk for severe and lingering adverse reactions to vaccines.

The onset of adverse reactions to conventional vaccinations (or other inciting drugs, chemicals, or infectious agents) can be an immediate hypersensitivity or anaphylactic reaction, or can occur acutely (24-48 hours afterwards), or later on (10-45 days) in a delayed type immune response often caused by immune-complex formation. Typical signs of adverse immune reactions include fever, stiffness, sore joints and abdominal tenderness, susceptibility to infections, central and peripheral nervous system disorders or inflammation, collapse with autoagglutinated red blood cells and jaundice, or generalized pinpoint haemorrhages or bruises.  Liver enzymes may be markedly elevated, and liver or kidney failure may accompany bone marrow suppression. Furthermore, recent vaccination of genetically susceptible breeds has been associated with transient seizures in puppies and adult dogs, as well as a variety of autoimmune diseases including those affecting the blood, endocrine organs, joints, skin and mucosa, central nervous system, eyes, muscles, liver, kidneys, and bowel. It is postulated that an underlying genetic predisposition to these conditions places other littermates and close relatives at increased risk. Vaccination of pet and research dogs with polyvalent vaccines containing rabies virus or rabies vaccine alone was recently shown to induce production of antithyroglobulin autoantibodies, a provocative and important finding with implications for the subsequent development of hypothyroidism (Scott-Moncrieff et al, 2002).

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Vaccination also can overwhelm the immunocompromised or even healthy host that is repeatedly challenged with other environmental stimuli and is genetically predisposed to react adversely upon viral exposure. The recently weaned young puppy or kitten entering a new environment is at greater risk here, as its relatively immature immune system can be temporarily or more permanently harmed. Consequences in later life may be the increased susceptibility to chronic debilitating diseases.

As combination vaccines contain antigens other than those of the clinically important infectious disease agents, some may be unnecessary; and their use may increase the risk of adverse reactions. With the exception of a recently introduced  mutivalent Leptospira spp. vaccine, the other leptospirosis vaccines afford little protection against the clinically important fields strains of leptospirosis, and the antibodies they elicit typically last only a few months. Other vaccines, such as for Lyme disease, may not be needed, because the disease is limited to certain geographical areas. Annual revaccination for rabies is required by some states even though there are USDA licensed rabies vaccine with a 3-year duration. Thus, the overall risk-benefit ratio of using certain vaccines or multiple antigen vaccines given simultaneously and repeatedly should be re-examined. It must be recognized, however, that we have the luxury of asking such questions today only because the risk of disease has been effectively reduced by the widespread use of vaccination programs.

Given this troublesome situation, what are the experts saying about these issues? In 1995, a landmark review commentary focused the attention of the veterinary profession on the advisability of current vaccine practices. Are we overvaccinating companion animals, and if so, what is the appropriate periodicity of booster vaccines?  Discussion of this provocative topic has generally led to other questions about the duration of immunity conferred by the currently licensed vaccine components.

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In response to questions posed in the first part of this article, veterinary vaccinologists have recommended new protocols for dogs and cats. These include: 1) giving the puppy or kitten vaccine series followed by a booster at one year of age; 2) administering further boosters in a combination vaccine every three years or as split components alternating every other year until; 3) the pet reaches geriatric age, at which time booster vaccination is likely to be unnecessary and may be unadvisable for those with aging or immunologic disorders.  In the intervening years between booster vaccinations, and in the case of geriatric pets, circulating humoral immunity can be evaluated by measuring serum vaccine antibody titers as an indication of the presence of immune memory. Titers do not distinguish between immunity generated by vaccination and/or exposure to the disease, although the magnitude of immunity produced just by vaccination is usually lower (see Tables).

Except where vaccination is required by law, all animals, but especially those dogs or close relatives that previously experienced an adverse reaction to vaccination can have serum antibody titers measured annually instead of revaccination. If adequate titers are found, the animal should not need revaccination until some future date. Rechecking antibody titers can be performed annually, thereafter, or can be offered as an alternative to pet owners who prefer not to follow the conventional practice of annual boosters. Reliable serologic vaccine titering is available from several university and commercial laboratories and the cost is reasonable.

Relatively little has been published about the duration of immunity following vaccination, although new data are beginning to appear for both dogs and cats.

Our recent study (Twark and Dodds, 2000), evaluated 1441 dogs for CPV antibody titer and 1379 dogs for CDV antibody titer. Of these, 95.1 % were judged to have adequate CPV titers, and nearly all (97.6 %) had adequate CDV titers. Vaccine histories were available for 444 dogs (CPV) and 433 dogs (CDV). Only 43 dogs had been vaccinated within the previous year, with the majority of dogs (268 or 60%) having received a booster vaccination 1-2 years beforehand. On the basis of our data, we concluded that annual revaccination is unnecessary. Similar findings and conclusions have been published recently for dogs in New Zealand (Kyle et al, 2002), and cats (Scott and Geissinger, 1999; Lappin et al, 2002).

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When an adequate immune memory has already been established, there is little reason to introduce unnecessary antigen, adjuvant, and preservatives by administering booster vaccines. By titering annually, one can assess whether a given animal's humoral immune response has fallen below levels of adequate immune memory. In that event, an appropriate vaccine booster can be administered.

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References

1. Dodds WJ. More bumps on the vaccine road.  Adv Vet Med  41:715-732, 1999.

2. Dodds WJ.  Vaccination protocols for dogs predisposed to vaccine reactions. J Am An Hosp Assoc 38: 1-4, 2001.

3. Hogenesch H, Azcona-Olivera J, Scott-Moncreiff C, et al.  Vaccine-induced autoimmunity in the dog. Adv Vet Med  41: 733-744, 1999.

4. Hustead DR, Carpenter T, Sawyer DC, et al. Vaccination issues of concern to practitioners. J Am Vet Med Assoc  214: 1000-1002, 1999.

5. Kyle AHM, Squires RA, Davies PR. Serologic status and response to vaccination against canine distemper (CDV) and canine parvovirus (CPV) of dogs vaccinated at different intervals. J Sm An Pract, June 2002.

6. Lappin MR, Andrews J, Simpson D, et al. Use of serologic tests to predict resistance to feline herpesvirus 1, feline calicivirus, and feline parvovirus infection in cats. J Am Vet Med Assoc 219: 38-42, 2002.

7. McGaw DL, Thompson M, Tate, D, et al. Serum distemper virus and parvovirus antibody titers among dogs brought to a veterinary hospital for revaccination. J Am Vet Med Assoc 213: 72-75, 1998.

8. Paul MA.  Credibility in the face of controversy.  Am Anim Hosp Assoc Trends Magazine XIV(2):19-21, 1998.

9. Schultz RD.  Current and future canine and feline vaccination programs.  Vet Med 93:233-254, 1998.

10. Schultz RD, Ford RB, Olsen J, Scott F.  Titer testing and vaccination: a new look at traditional practices. Vet Med, March 2002, pp 1-13.

11. Scott FW, Geissinger CM. Long-term immunity in cats vaccinated with an inactivated trivalent vaccine. Am J Vet Res 60: 652-658, 1999.

12. Scott-Moncrieff JC, Azcona-Olivera J, Glickman NW, Glickman LT, HogenEsch H. Evaluation of antithyroglobulin antibodies after routine vaccination in pet and research dogs. J Am Vet Med Aassoc 221: 515-521, 2002.

13. Smith CA.  Are we vaccinating too much?  J Am Vet Med Assoc  207:421-425, 1995.

14. Tizard I, Ni Y.  Use of serologic testing to assess immune status of companion animals. J Am Vet Med Assoc 213: 54-60, 1998.

15. Twark L, Dodds WJ. Clinical application of serum parvovirus and distemper virus antibody titers for determining revaccination strategies in healthy dogs. J Am Vet Med Assoc 217:1021-1024, 2000.

Statement / BY-Line

Vaccinations for the new puppy ...

One of the most controversial issues in veterinary science today concerns vaccinations. What people are questioning is the frequency of vaccination, some safety vs. efficacy concerns and even whether to vaccinate at all. So when you ask your vet when to bring your new puppy back for its next shot, be aware there is no one correct answer. How often to vaccinate will depend upon quite a few different factors. Some of these considerations include your puppy's environment, its breed, the age at which the first shot was given and the interval between shots. Also important are the kinds of vaccines necessary for the area you live in and what type, e.g., whether a killed, recombinant or a modified live-type vaccine is being used.

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The Vaccine Controversy

The first point to consider is the safety issue. Vaccines can be harmful. We vaccinate because the advantages outweigh the risks. Just ask anyone who has seen a beloved pet die of parvo or distemper. But one should question the sense of vaccinating against Lyme disease or leptospirosis in an area where these diseases are not a problem. This is why the dog's environment is so important. High-risk dogs are those that live in close proximity with each other, as in a shelter or kennel situation, or show dogs constantly exposed to dogs from all over the country. These are the animals that should be getting vaccinated every six months for such diseases as bordetella bronchiseptia (a strain of kennel cough) and parainfluenza. A case might even be made for vaccinating the high-risk dog against corona virus. But there are risks associated with vaccinations and when weighed against the benefits such risks usually are considered acceptable, except when it is your dog that suffers the untoward reaction. For instance some dogs, after being vaccinated with modified live canine distemper vaccine (see types of vaccines) can develop aggression, seizures, a lack of coordination and other neurological dysfunctions caused from a rare condition called postvaccinal canine distemper virus encephalitis. Another problem noted with genetically susceptible animals is that it is possible for vaccinations to trigger various autoimmune diseases, including several blood disorders and a rabies vaccine-induced encephalitis.

Another source of controversy is the recommended frequency of vaccinations. Although yearly boosters are recommended by most vets, for many diseases the yearly booster really is not obligatory. However, a yearly checkup is necessary for the same reasons you would have one yourself. For the low-risk pet, once the initial puppy series is completed, a booster at one year and another at three years should suffice until your dog's senior years. Unfortunately, no duration of efficacy studies are available yet because minimum duration studies were not required for vaccine licensure until recently. This means there really are no data that tell us how long the immunity lasts in a vaccinated animal, but animal vaccines should compare favorably with the duration of human vaccines. On the other hand, no data supports yearly vaccinations either. 

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Why Is Breed Important?

If your puppy is a Rottweiler, Greyhound or Doberman, or even a mix of one of these breeds, you should be aware that the normal series of shots for parvovirus may not be enough to produce noticeable antibody titer. It may take multiple shots given over a year's time before your dog is protected adequately. Why is that, you ask? At this point no one is quite sure. The basis most likely is genetic because it seems more prevalent in certain lines, but some data indicate that upward of 5 percent of Rottweilers are going to be poor responders. On the other hand, the immune system is very complex, and just because the antibody titer is low does not mean the dog will not survive exposure to the disease.

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A Short Course In Immunology

So what is antibody titer? Antibody titer is going to be the new veterinary buzzword. Simply put, when your body is exposed to a foreign protein such as the outer coat of a virus or bacteria, your immune system is able to recognize that this is a foreign body. Why? Because everyone carries on most cells a glycoprotein (a sugar-protein molecule) that identifies his or her cells as unique to himself or herself. These molecules are called the Major Histocompatibility Complex I and II proteins, and why they are important will become clear later in this article. Once an invasive agent is recognized as ëaliení, your body is able to mount a specific immune response that targets that precise foreign protein. This is called the humoral response and involves the making of antibodies. An antibody is another protein whose job is to attach itself to the target molecule so another type of cell, called a macrophage, can eliminate it. However, the body takes quite a while to mount this specific immune response on the first exposure to an antigen, or more correctly an epitope. Epitope is "science speak" for a fragment of a foreign protein. This immune system learning process is the reason why both you and your puppy get multiple vaccinations during the first initial series. After being exposed once to a particular antigen (which is antibody-generating), some of these cells turn into memory cells with the ability to manufacture antibodies against that specific antigen with a much shorter response time. Once firmly established, immunity against the particular antigen can last a very long time, sometimes for the entire lifetime of the animal.

The humoral response is just one way the immune system defends the body against pathogens. There are the native defense mechanisms such as the complement system, enzymes in the saliva and tears, acids in the stomach and even beneficial bacteria in the gastrointestinal tract that can be considered the first line of defense. For our purpose here, with respect to vaccinations, the other most important immune response is known as cell-mediated immunity. This type of immunity is the result of the interaction of several different types of white blood cells and is controlled by a class of cells called T- cells. Some pathogens, such as viruses, have learned to hide from the immune system by inserting themselves into different types of body cells. Once established within the cell the virus can either go dormant or proceed to take over the genetic replication machinery of the host cell. It is possible for the body to recognize those host cells infected by virus because certain changes occur on the affected cell surface that alert the T-cells to the presence of virus. Once aware of the threat, the cytotoxic T-cells either destroy the infected host cell or secrete an array of protein molecules that can eliminate targeted host cells. However, cytotoxic T-cells only will attack virus-infected host cells if they are expressing MHC class I molecules on their surface. A virus-infected cell also will release a glycoprotein called interferon. Not only does interferon have antiviral activity, but its presence induces the production of two other proteins that inhibit viral reproduction.

Current thinking suggests that when vaccination is known to prevent reinfection, it is the humoral system that is regulating protection. However, it appears cell-mediated immunity is the primary regulator of vaccines that prevent clinical expression of disease but do not always prevent reinfection. Hence, the ideal vaccine should elicit both types of immune response.

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Types of Vaccines

Killed vs. Modified Live

When designing a vaccine, efficacy and safety are the primary considerations. These two principles appear to be mutually incompatible. In order to offer immunity against disease the vaccine model should mimic the native antigen and yet should not cause pathology, i.e., clinical signs of disease. Killed vaccines, also known as fully attenuated vaccines, until recently have been the safest vaccine option available. They are safer because unlike the modified live vaccines they do not shed virus into the environment nor can they ever revert to virulence. However, in order to maximize their effectiveness, killed vaccines are normally used with adjuvants that can cause their own problems. The immune system is antigen-driven. This means that in order to mount an effective immune response, the body must ëseeí the antigen for as long as possible. Once the antigen is eliminated the response is terminated. Many different compounds have been used to enhance the efficacy of killed vaccines, but the rational behind their use is to prolong the antigenic stimulus of the primary immune response.

In comparison, the modified live vaccines are more like the original pathogen in the way they elicit a immune reaction. In general, vaccines that contain the living organisms will produce a stronger and a longer-lasting immunity, but their virulence must be reduced to a safe level. This process is called attenuation. Reducing the virulence of bacteria is accomplished by culturing them under unusual conditions. For example, one can make them dependent on a growth medium that is not available in the living animal so they cannot reproduce. Once introduced into the body these bacteria can elicit the expected immune response, but die off so rapidly they do not cause the disease. When the pathogen is a virus a different strategy is used-cell culture in cells or in a species for which the organism is not normally adapted. After many passages through these foreign cell lines the virus is unable to produce disease when reintroduced into its original host. Another issue associated with the use of MLV is possible contamination with other pathogens. One also should be aware this not just one organism, but a population. Therefore it is conceivable that deleterious mutations might occur. So you can see there are problems associated with both types of vaccines and some choices between safety and efficacy that need to be made.

Recombinant

Great strides have been made in recombinant technology and the future will bring even more advances leading to vaccines that may offer better protection and greater safety. A recombinant is defined as a virus, a bacterium or other microorganism in which the genetic material has been artificially modified. This alteration usually involves deletion of all or part of a gene or the insertion of one or more genes from another organism. So far the United States Department of Agriculture has classified three different types of recombinant vaccines.

The first class is called Subunit Vaccines. It really is not necessary for an animal's immune system to "see" the entire infectious organism in order to mount an immune response. Often all that is required is for only a small portion or protein fragment to act as the antigen. An example of a subunit vaccine is one developed by Rhone Meriux scientists (now known as Merial) against Lyme disease. This vaccine is made of purified Outer surface protein A. After mapping the genome of the bacteria Borrelia burgdorferi, it was determined that this protein evoked the greatest antigenic response. Recombinant techniques allow for the isolation of this DNA fragment and its amplified expression. It then is purified and used to manufacture the vaccine. Besides safety, one of the greatest advantages of this type of vaccine is that a simple blood test can distinguish between animals that have been vaccinated and those that are infected naturally.

The second category is recombinant: Gene-Deleted vaccines. These can be considered a type of genetically attenuated modified live vaccine. Those parts of the pathogen that can cause disease are either removed or rendered nonfunctional.

The third type is called Recombinant: Vectored Vaccines. Recombinant techniques are used to isolate and remove the immune-inducing genes from a pathogenic virus. These genes then are inserted into a nonvirulent vector virus. Once innoculated into the host the vector virus produces both its genes and those of the 'crippled' pathogenic virus. This has the potential to be a very effective type of vaccine because both a humoral and a cell-mediated immune response are elicited. Class III vaccines may also allow for alternative methods of vaccination, for instance, an oral mode of administration. They also have the potential for immunization against more than one type of infection. The advances in safety and efficacy made possible by this new technology bode well for the future health of our pets.

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Vaccine Failure

It may require one to two weeks or more to develop an effective immune response after a course of vaccination. If the animal is exposed to an infectious agent prior to vaccination or shortly after, the vaccine will not have had time to induce immunity and the puppy will develop clinical signs of the disease. This also will occur if the puppy was incubating the disease at the time it was vaccinated. In fact, the modified live vaccines can cause something called immunosuppression, so vaccinating a puppy that already is sick only will make matters worse. Canine parvovirus, canine distemper and the use of polyvalent vaccines that contain these attenuated viruses have been implicated in inducing immune dysfunction. Other factors that can cause immunosuppression are stresses including pregnancy, malnutrition, concurrent infections, not allowing enough time between scheduled vaccinations and the use of drugs such as prednisone. Another cause of vaccine failure is incorrect administration, including splitting a vial between puppies.

However, the most common reason for vaccine failure is thought to be the presence of maternal antibodies. This is a passive immunity gained from the dam's colostrum during the first 72 hours of nursing. Maternal antibody interferes more with viral vaccines than bacterial vaccines and with the parvovirus vaccines more than any other type of viral vaccine. Unfortunately, the amount of antigen that causes disease is less than that needed to overcome maternal antibodies, so there is a period of vulnerability when the protection afforded by maternal antibodies is not sufficient to prevent disease and the puppy's immune system is not yet fully functioning. It is very important not only to isolate the puppy from contact with other dogs, but to maintain a strict hygienic regime. A bleach solution diluted 1:10 with water will kill even the parvo virus, but remember to thoroughly rinse with clean water before allowing the puppy to contact a bleached surface. Urine mixed with bleach can cause a chemical reaction and the production of chlorine gas.

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A Possible Vaccination Schedule For The Low-Risk Puppy

With the stipulation previously mentioned that there is no one correct vaccination protocol and that each individual animal's needs should be assessed by its veterinarian, what follows is an example of an optimal vaccination schedule.

Ideally the initial vaccination should begin no earlier than 6 weeks of age with a modified live measles/distemper vaccine. Measles? Yes, measles. This is an example of a process called heterotypic immunity. It is possible to induce an immune response to one microorganism by immunizing with another microorganism. Since the measles virus is antigenically related to (the body sees it the same way as) the distemper virus, it is possible to confer temporary protection against distemper while avoiding interference from distemper maternal antibodies.

The second shot should be a modified live parvovirus vaccine given 10 days to two weeks after the first injection. At 10 weeks the first MLV distemper shot may be given by itself; however, a combination parvo and class III recombinant distemper vaccine now is available, so this also is an option. Most practitioners also will recommend the puppy be inoculated against canine adenovirus type 2 (CAV-2), which causes a respiratory tract disease. This vaccine will cross-protect against infectious canine hepatitis as well. In some rare cases, if given jointly with the distemper MLV, it can cause temporary immunosuppression. If you are not using the recombinant distemper alternative, then at 12 weeks another MLV inoculation against parvovirus and at 14 weeks a combined CDV/ CAV-2 shot should be given. The use of low passage/high titer vaccines now have made it possible to overcome maternal antibody vaccine inactivation at an earlier age and thus shorten the window of vulnerability to canine parvovirus, but remember greater efficacy means you lose some safety factors.

Most veterinarians will vaccinate every two weeks, although a three- or four- week interval is considered optimal. At four months, those dogs that will be shown or kenneled should have the intranasally administered modified live parainfluenza and Bordetella bronchiseptica vaccines. At six months a rabies vaccination is required by law. A killed rabies vaccine in the most commonly given and the preferred route is intramuscular.

There is no question that one should vaccinate. Vaccinations protect both the individual dog and the canine population as a whole. What you as a pet health consumer should be aware of is that there are some very real concerns within the veterinary community on the vaccination issues. It is difficult to obtain agreement among academics as to the necessity of certain vaccines, much less the question of yearly vaccinations. You will find just as little consensus among practitioners, but it is you, the puppy owner, who needs to make the final decision.

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Bibliography

1. Everman, J.D.; McKeinan A.J.; Eugster, A.K.; et al. Update on canine coronavirus infections and interactions with other enteric pathogens of the dog. Companion Animal Practice. 1989;19(2):6-12.
2. Jarecki-Black, J.C.. Personal Communication.
3. Krakowka, S. et al. Canine Parvovirus Invection Potentiates Canine Distemper Encephalitis Attributable to Modified-Live Virus Vaccine. Journal of the American Veternary Medical Association. 180:137-139, 1982.
4. Marwick, C. Exciting potential of DNA vaccines explored. JAMA 273(18):1403-1404, 1995.
5. Mastro, J.M.; Axthem, M.; Mathes, L.E.; et al. Repeated suppression oflymphocyte blastogenesis following vaccination of CPV-immune dogs withmodified-live CPV vaccine. Vet Microbio. 12:201-211, 1986.
6. Norrby E.; Utter G.; Orvell C.; et al. Protection against canine distemper virus in dogs after immunization with isolated fusion protein. J Virol 58: pp 536-541, 1986.
7. Ogilvie, Greg, D.V.M. Journal of the American Veterinary Medical Association, vol 203, pages1144-1146, 1993.
8. Robinson, A., DNA based vaccines: New possibilities for disease prevention and treatment. J Can Med Assoc. 152(10) 1692-1632, 1995.
9. Schultz, R.D. Current and Future Vaccination Programs. Veterinary Medicine. In Press Schultz, R.D. Canine Vaccines and Immunity: Important Considerations in the Success of A Vaccination Program. Personal Communication.
10. Thorpe-Vargas, S.; Cargill, J.C. Vital Vaccinations. DOG WORLD Magazine. Feb. 1996, pp 38-45.
11. Tizard, Ian R., Ph.D., B.Sc., B.V.M. Veterinary Immunology: An Introduction. 5th Ed., W.B. Saunders Company, Philadelphia, Pa. 1996.
12. Tizard, I. Risks Associated with the Use of Live Vaccines. Journal of the American Veterinary Medical Association. 196:11 pp1851-1858, 1990.